The Oct1 (POU2F1) transcription factor is a potent regulator of metabolism and tumorigenicity. Oct1 promotes glycolysis at the expense of mitochondrial metabolism, a metabolic profile indicative of stem cells and tumor cells. Loss of Oct1, either by germline deletion or RNAi, augments mitochondrial function and antagonizes transformation in vitro and tumor growth in vivo. Loss of Oct1 also sensitizes cells to ionizing radiation (IR), H2O2 and doxorubicin. Our new findings show that Oct1 is highly expressed in stem cells, which tend to be chemo- and radio-resistant. We have identified a pathway in which Oct1 phosphorylation couples stress inputs to transcriptional output through altered target selectivity. Our preliminary findings show that loss of Oct1 specifically depletes cancer stem cell populations as measured using two criteria. We propose to identify how Oct1 regulates metabolism and "stemness" to control cancer onset and progression: 2.1. Specific Aim 1: Determine whether Oct1 functionally controls cancer stem cell identity 2.2. Specific Aim 2: Identify Oct1 activities and targets underlying the stem cell phenotype PUBLIC HEALTH RELEVANCE: The most exiting aspects of this work are the potential to verify a role for Oct1 in the control of stem cell identify in adult normal and malignant cells and to identify Oct1 transcription targets that underlie the observed stem cell phenotypes. If successful, these studies will place Oct1 and components of Oct1-regulated pathways in a category of targets that may be suitable for cancer therapies. Therefore, we feel that this proposal has a strong possibility of moving the field forward.